5 SWISS PHARMA SCIENCE DAY th SWISS PHARMA SCIENCE DAY 2014 at the University of Bern on August 20, 2014 The SWISS PHARMA SCIENCE DAY Key annual event of the Swiss Society of Pharmaceutical Sciences (SSPhS) Registration for the 7 th SWISS PHARMA SCIENCE DAY is now open through the website of the Swiss Society of Pharmaceutical Sciences (SSPhS; The SWISS PHARMA SCIENCE DAY (SPhSD) is an annual event of the Swiss Society of Pharmaceutical Sciences (SSPhS). The 1 st SPhSD was held on October 9, 2008, at the University of Bern. For congress reports including all lecture and poster abstracts see SWISS PHARMA 10/2008, 10/2009, 10/2010, 10/2011, 10/2012, and 10/2013 or The SPhSD offers a platform to present, in form of a poster session, the latest research results of Master and PhD students, as well as Post-Docs of all the three Swiss Academic institutions for Pharmaceutical Sciences (ETH Zurich, School of Pharmaceutical Sciences of the Universities of Geneva and Lausanne EPGL in Geneva, and the University of Basel). Master students of the Universities of Applied Sciences, i.e. FHNW (School of Life Sciences, Muttenz BL) and ZHAW (Life Sciences and Facility Management, Institute of Biotechnology, Wädenswil ZH) are also invited to participate in this event. The poster session is embedded in a series of lectures given by invited distinguished scientists representing the broad field of pharmaceutical sciences, such as Pharmaceutical Biology, Biotechnology, Technology, Chemistry, Analytics, Engineering, Pharmacology, or Molecular Biology. One of the primary goals of the SPhSD is to further stimulate professional and social contacts between the students still undergoing training, and Alumni, having already a position in industry, hospital, public health administration or public pharmacy. Thus, cooperation and networking between the different institutions in academia and industry and the different fields of pharmaceutical sciences is being promoted. Last but not least, the SPhSD represents an ideal platform to meet young engineers and scientists, who may be recruited for a position in the academia, hospital, industry, public health administration or public pharmacy. Speaker at the 7 th SPhSD: Prof. em. Daan J.A. Crommelin, Ph.D Prof. Daan Crommelin is emeritus-professor at the Department of Pharmaceutics at Utrecht University. Until December 2011 he was scientific director of the Dutch Top Institute Pharma in Leiden. He is adjunct professor at the Department of Pharmaceutics and Pharmaceutical Chemistry at the University of Utah. Crommelin is co-founder of OctoPlus, a Leiden based company specialized in the development of pharmaceutical product formulations and advanced drug delivery systems. He published extensively and is on the editorial board of 10 peer reviewed journals in the pharmaceutical sciences. He also advises venture capital groups. He chaired the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation (F.I.P.), was chair of the organizing committee of the Pharmaceutical Sciences World Conference 2007 in Amsterdam. He is past president of the European Federation of Pharmaceutical Sciences (EUFEPS) and past vice-chair of the scientific advisory board of the European Innovative Medicines Initiative (IMI). SWISS PHARMA 36 (2014) Nr. 3 3

7 Pharmaceutical Production / Biotherapeutics / Blood plasma products The therapeutic blood plasma proteins: History, patient benefits and the role and contributions of Swiss companies to the progress and success of this little known business sector Ruedi E. Wäger, Ph. D. (Swiss Federal Institute of Technology, Zurich), Vandoeuvres / Geneva, Switzerland The human blood plasma in which the blood cells (red cells, platelets etc.) are suspended and transported contains thousands of proteins. Many of those have been characterized, but the therapeutic use has been assessed for only a few of these proteins (factor VIII, factor IX, albumin, immunoglobulins etc.). These products, which are manufactured by highly specialized companies, have saved millions of patient lives and improved the quality of life for many more millions of people. The isolation and purification of therapeutic proteins from human plasma is a relatively young science. The breakthroughs happened in the 1940ies during World War II. Since then, the scientific and industrial activities increased significantly worldwide and new or improved products were and are made available for doctors and patients. Unfortunately, the patients and the industry suffered a dramatic set-back in the early 1980ies when the contamination of blood plasma products by viruses (HIV, hepatitis) and the infection of patients in need of these products were discovered. These extremely dramatic and sad events could finally be overcome by huge efforts of the industry (plasma donor selection, sophisticated blood testing technologies, plasma tracking, virus inactivation technologies etc.). No single patient infection by any product from any manufacturer with very high safety and quality standards has been reported since years. The blood plasma industry and its technologies for the isolation and purification of therapeutic proteins made a significant contribution to the origin of the biotechnology sector which focuses on the research, development and application of human proteins, monoclonal antibodies, enzymes etc. manufactured in cell cultures for therapeutic purposes. Several companies in Switzerland pioneered the development of the blood plasma industry by innovative manufacturing technologies, products and blood testing approaches. In addition, Switzerland is still a worldwide important manufacturing site for blood plasma products with the highest safety and quality standards. The present paper tries to offer an overview on the therapeutic proteins from blood plasma and the industry, which is not well known in Switzerland since this business is relatively small, compared to Switzerland s global leadership in the pharmaceutical industry. 1. Introduction Blood stood in most cultures and religions for the essence of life and played a mystic role of divine presence in human life. Therefore, it does not astonish that medicine already in early cultures turned its interest to human blood as a potential magic bullet for the therapy of human diseases. It is well known that already the Greek physicians used blood for the treatment of epilepsy and the efforts to use blood as a therapeutic principle continued until the beginning of the 20 th century quite often with fatal consequences. Finally, the discovery of the blood groups by Karl Landsteiner in 1901 opened the way and the beginning of transfusion medicine. Since then, it was possible to treat patients with acute blood loss due to accidents, surgeries etc. successfully by transfusion of compatible human blood components, especially red blood cells. This was a real breakthrough and it opened the way to save millions of human lives by transfusion of red cells. The therapeutic use of the other blood components (e. g. blood plasma and its proteins, platelets for the coagulation and maintenance of hemostasis, stem cells etc.) was still far away at that time. The exploitation of the human blood plasma, a watery straw-colored fluid in which the erythrocytes (red cells), platelets and leukocytes are suspended and which contains water, electrolytes, essential proteins, glucose, fats, bilirubin and gases, had to wait until the 1940ies. With the isolation of the essential and life-saving proteins from blood plasma, a new era of enthusiasm and hope started for physicians and patients as well. These discoveries should also open the door for modern biotechnology, i. e. the production and isolation of therapeutic agents SWISS PHARMA 36 (2014) Nr. 3 5

8 Pharmaceutical Production / Biotherapeutics / Blood plasma products (proteins, enzymes. monoclonal antibodies etc.) from cell cultures for therapeutic purposes. The real pioneer work was achieved in the United States at the university and industry level but Germany and Switzerland were early followers and played an important role in the development of transfusion medicine and the development and production of innovative therapies from human blood plasma. In addition, many initiatives for the improvement of the safety and quality of blood products, especially regarding the reliable testing procedures for blood/plasma donations, were initiated in this country. Switzerland plays still a worldwide leading role in this industry though this is not broadly recognized due to the fact that our worldwide leading and successful pharmaceutical and diagnostic companies attract so much attention for good reasons by the way. The following chapters try to describe the history, success and problems of this not very well known business sector and to illustrate its contributions to the benefit of patients and the development of modern therapies by biotechnological approaches. 2. The first isolation and purification of plasma proteins 40 years after the breakthrough in transfusion medicine with recipient-compatible red cell products (concentrates of erythrocytes) and in midst of World War II which challenged the medical support of the civilian population and the soldiers around the world, Prof. Edwin J. Cohn and his associates at Harvard Medical School (1), succeeded in 1940 to isolate the first plasma proteins. They developed a fractionation process (precipitation of plasma proteins with ethanol at various ph levels in a cold environment). The first product was albumin, the most prominent protein in human blood plasma which is used for the stabilization of the blood circulation after blood loss e. g. after surgery, accidents, burns etc. The work of Prof. Cohn and his associates was a scientific masterpiece and a true pioneer achievement, which helped to save the life of millions of people during World War II. By the way, Prof. Cohn never asked for any patent protection for his discovery and shared the results of his research broadly with scientists, universities and the industry. He was twice a candidate for the Nobel Prize award. His technology is still used worldwide of course with many modifications and improvements which were achieved over time. Due to the fact that there was an urgent medical need to provide the victims of the war, the great achievement and discovery of Prof. Cohn and his associates was immediately followed by the pharmaceutical industry: Cutter Laboratories, a manufacturer of vaccines in Berkeley, California (acquired by Bayer AG, Leverkusen, in 1978), Miles Laboratories in Elkart, Indiana (acquired by Bayer AG, Leverkusen, in 1979), Armour Pharmaceutical Company in Chicago, Illinois (acquired by Rhône-Poulenc Rorer in 1979) and later Baxter Inc. (today Baxter Bioscience) in Deerfield, Illinois, started to apply the discoveries of Prof. Cohn to the industrial fractionation and purification of blood plasma proteins. Some of these companies (especially Armour Pharmaceutical Company) had already worked with Prof. Cohn in the 1930ies. In Germany, Behringwerke (later part of Centeon/Aventis Behring, today part of CSL Behring) began the fractionation and purification of plasma proteins in 1942 and became one of the most innovative and successful companies in this worldwide industry. Behringwerke isolated many additional plasma proteins and developed those to still leading specialty products. In addition, Behringwerke developed the first pasteurized/heat treated factor VIII product in the early 1980ies: this product (Haemate) was the best answer to the potential threat of virus contamination of hemophilia patients (hepatitis, HIV). Unfortunately, at the beginning not enough product could be manufactured to replace other less safe factor VIII products. By the way, the founder of Behringwerke, Prof. Emil von Behring, was the first scientist to receive the Nobel Price for Medicine and Physiology for his development of diphtheria serum therapy in Modern plasma donation center automatic plasmapheresis station 6 SWISS PHARMA 36 (2014) Nr. 3

9 Pharmaceutical Production / Biotherapeutics / Blood plasma products Despite the fact that Prof. Cohn and his associates were successful to isolate and purify the most important plasma proteins, only albumin could be used for therapeutic purposes but this was already a first big breakthrough in times of war. Prof. Cohn and his associates were also able to isolate factor VIII for the treatment of hemophilia A, a rare but devastating genetic disorder, and immunoglobulins (a concentrate of all antibodies available in blood plasma) for the treatment of patients with a deficiency of the immune system or suffering from autoimmune diseases. However, these two products were not yet ready for the therapeutic treatment of patients. Additional efforts were necessary to open plasma proteins the access to the therapy of patients. J.G. Poole (2) and E. Remigy (3) made an important contribution to the therapy of hemophilia A patients with factor VIII: They discovered that the cold-insoluble portion of frozen plasma (cryoprecipitate) was rich in therapeutically useful factor VIII. This discovery opened the way for blood transfusion centers and blood banks to prepare a concentrate of factor VIII and the plasma industry followed with the purification of factor VIII harvested from cryoprecipitate. 3. The pioneer role of Switzerland in the early beginnings of transfusion medicine and plasma protein therapy There is no doubt that the Swiss Red Cross had a wonderful vision to found the Swiss Blood Transfusion Service for the supply of the hospitals and patients in our country with the amount of blood products (red cells, platelets, fresh-frozen plasma) needed and at a high and reliable level of quality and safety. The Blood Transfusion Service of the Swiss Red Cross collected in local blood centers and with mobile teams enough blood from volunteer donors to guarantee the countrywide supply with the blood products needed. The Blood Transfusion Service of the Swiss Red Cross did an extremely good job to motivate the population to donate blood and created a great awareness for this act of solidarity with the patients all over Switzerland. To donate blood was and may still be for many Swiss citizens a natural service to the community. In addition to the Blood Transfusion Service of the Swiss Red Cross, the not-for-profit foundation ZLB, Central Laboratory of the Blood Transfusion Service Swiss Red Cross in Bern, played a very particular and critical role: ZLB was responsible for collecting the blood of volunteers outside the cities and hospital collection centers all over Switzerland, including the members of the army in service each year. In addition, ZLB developed into a center of excellence for diagnostics with a particular emphasis on blood screening for infectious diseases: hepatitis A, B, C, HIV etc.. ZLB also took care of the Swiss registry of bone marrow donors and coordinated the exchange of those informations/donations worldwide. The big name behind the success of ZLB was Prof. Alfred Hässig, M.D.. He developed ZLB to a nationally and internationally recognized center of reference in blood transfusion. With his great scientific network he was able to build important alliances, e. g. the supply of the New York Blood Center (the City of New York suffered always from the short supply of red cells) with erythrocyte concentrates while the plasma remained in the country for being processed into life-saving drugs. The strict U.S. importation rules and the necessary inspections by the Food and Drug Administration (FDA) helped the ZLB to achieve a very high level of quality and safety management at an early stage. In addition, Prof. Hässig organized the supply of red blood cells to Southern European countries: Those products were necessary for the treatment of thalassemia (anemia due to deficient hemoglobin synthesis/short-lived abnormal red cells). Finally, Prof. Hässig realized very early that it did not make any sense to use just the blood cells and to waste most of the plasma (except the fresh-frozen plasma) and all the proteins. He accelerated the manufacturing of albumin and factor VIII and invested in R+D efforts with the aim to develop a well-tolerated immunoglobulin for the treatment of deficiencies of the immune system and autoimmune diseases. These efforts resulted in the launch of one of the first immunoglobulins worldwide. Prof. Silvio Barandun, M.D., immunologist at the University of Berne, was the most prominent partner of ZLB and Prof. Hässig: He described with Prof. Hässig et al. for the first time the antibody deficiency syndrome. The newly Most recent centrifugation technology (Westfalia) SWISS PHARMA 36 (2014) Nr. 3 7

10 Pharmaceutical Production / Biotherapeutics / Blood plasma products A medical interview with the plasma donor takes place prior to each plasma donation developed immunoglobulin manufactured by ZLB was launched and distributed worldwide by Sandoz Pharmaceuticals Inc. (today Novartis) under the trade name Sandoglobulin. Sandoglobulin was an international success by saving thousands of lives of patients in need of treatment with antibodies. Another pioneer contribution of ZLB was the development of a new fractionation process. Dr. Peter Kistler (ZLB) and Prof. Hans Nitschmann (University of Berne) were able to develop a more simple fractionation scheme, which resulted in higher yields of plasma proteins (4). Dr. Hans Friedli (ZLB) improved this procedure, the socalled Kistler-Nitschmann process, further by the introduction of a filtration step, which made the large-scale production of immunoglobulins still more simple and more productive. This manufacturing process is still in use today at CSL Behring and other manufacturers of plasma proteins worldwide (e. g. LFB in France). Between 1994 and 1998, ZLB was significantly transformed into a worldwide leading manufacturer of plasma proteins. The programs were aiming at a much higher productivity (e. g. 3 manufacturing shifts instead of 1), expansion of throughput capacity, upgrading of the infrastructure and the quality management systems, and higher investment in R+D. These efforts resulted in a significantly higher manufacturing output and a stronger worldwide marketing position as well as in the launch of a truly innovative ready-to-use anti-d hyperimmunoglobulin (with several virus inactivation steps), the advanced development of a new liquid (non-lyophilized) immunoglobulin and the development of a reconstituted HDL product. In addition, the distribution agreement with Novartis was renegotiated and opened the door to international marketing activities by ZLB itself. ZLB decided as a not-for-profit foundation to pay taxes for its industrial activities. All these efforts had a clear objective, namely to position ZLB much better for a successful growth in the international plasma business environment. The last step of the transformation process was the separation from all activities related to the blood transfusion service of the Swiss Red Cross in 1997: Those activities (blood collection by mobile teams all over Switzerland, blood screening/testing, reference laboratory, bone-marrow donor registry etc.) were transferred to the Blood Transfusion Service of the Swiss Red Cross. By these steps, ZLB mutated to an important industry player and was well prepared for a potential next step, namely to become a public company in Switzerland. Mrs. lic. iur. Elisabeth Kopp, President of the Board of Trustees, and PD Dr. Hans W. Schmid, member of the Board of Trustees, made a significant contribution to these developments by recognizing early the industrial potential of ZLB and by supporting its further growth and international development. In 2000, the founder of ZLB, the Swiss Red Cross, decided to sell ZLB to CSL (Commonwealth Serum Laboratories), Melbourne, Australia. CSL was already well established in the plasma protein and vaccine industry, but rather on a local or regional (Asia) level. Through the acquisition of ZLB in 2000 and the acquisition of Aventis Behring in 2005, CSL became one of the leading players in this worldwide industry and maintains important operations in Switzerland. It has to been mentioned that on top of ZLB and CSL Behring four other Swiss companies have made significant contributions to the advance of the worldwide plasma industry. First, F. Hoffmann La Roche (Roche Molecular Diagnostics) which bought the rights for the use and development of the PCR (polymerase chain reaction) technology for diagnostic purposes from Cetus Corporation. This technology is the gold-standard for the early and reliable detection of any virus infections of the blood and plasma donors. Prionics a spin-off of the University of Zurich pioneered the diagnostics of prion infections (Creutzfeldt-Jakob disease, mad cow disease). In addition, Octapharma, a leading manufacturer of plasma products, which is well known for its immunoglobulins and the virus-inactivated fresh frozen plasma, is headquartered in Switzerland. Octapharma maintains manufacturing operations in Austria, France, Germany, Sweden and Mexico and runs 54 plasma centers in the U.S. and in Germany. The Swiss Serum and Vaccine Institute ( Berna ) was during a long period of time an innovative and worldwide active manufacturer of immunobiological products. The company was acquired by Crucell in Innovations by the plasma industry and transition to the areas of recombinant products and biotechnology After the isolation and purification of the volume-wise most prominent plasma proteins (albumin, immunoglobulins, fibrinogen and factor VIII), the plasma industry kept its pace of innovations with new plasma proteins for the therapy of rather orphan diseases: factor IX for the treatment of hemophilia B (a rarer form than hemophilia A which is treated with factor VIII), antithrombin (AT III) for the therapy of antithrombin III deficiency, a rare hereditary disorder (the patients are suffering from recurrent venous thrombosis and / or pulmonary embolism), specific hyper-immunoglobulins for the treatment of virus infections (hepatitis etc.) as well as the treatment and prophylaxis of the incompatibility of the rhesus factors in pregnant women and babies (Anti-D immunoglobulin), alpha-1-antitrypsin for the therapy of patients with alpha-1-deficiency (a hereditary lung disease), C1-esterase inhibitor for the prevention of hereditary angioedema attacks in patients etc. Many additional products are actually under development. The most promising could be plasmin for the treatment of patients with peripheral arterial occlusions (POA) and victims of a cerebral stroke. Hundreds of other plasma proteins though available in much smaller quantities in plasma and whose functions are not always completely clear may wait for more research and development (e. g. plasmin, transferrin and others). In the 1970ies, Prof. Herbert W. Boyer succeeded with the manufacturing of insulin and somatotropin from cell cultures. This was the birth of the biotechnology era. Prof. Boyer was later the founder of Genentech, the leading biotechnology company of the world, which is today owned by F. Hoffmann-La Roche. The two most important plasma product manufacturers in the 1990ies, Baxter and Bayer, launched in 1992 and 2000 respectively the first recombinant plasma protein, namely factor VIII (Recombinate and Kogenate respectively). Those two recombinant products replaced very quickly the plasma-derived factor VIII products in the developed countries. The recombinant factor VIII products were considered to be safer, i. e. without any risk of virus contaminations for the patients concerned. This fact was very important for the hemophilia A patients who suffered most from the hepatitis and HIV infections 8 SWISS PHARMA 36 (2014) Nr. 3

11 Pharmaceutical Production / Biotherapeutics / Blood plasma products by blood plasma products in the early 1980ies. Wyeth/American Home Products developed a third, slightly modified recombinant factor VIII product and Genetics Institute/Baxter launched the first recombinant factor IX product. Genetics Institute was at that time in cooperation with important pharmaceutical companies like Sandoz and Schering-Plough the leader in developing and manufacturing recombinant interleukins and GM-CSF (granulocyte-macrophage colony stimulating factor), which played a major role in the treatment of cancer patients. Novo Nordisk was successful with the development and marketing of a recombinant factor VIIa for the prophylaxis and treatment of severe bleedings. Quite recently, GTC Therapeutics launched a recombinant antithrombin III (AT III) product for the treatment of antithrombin III deficiency. Most plasma proteins could and will be manufactured one day by recombinant technologies, i. e. in cell cultures. However, the most important product, immunoglobulin, which represents nearly all antibodies available in human blood and plasma respectively, will probably never be substituted by new technologies. Plasma fractionation is and remains for a long time the only source to provide patients in need with the antibodies they need for the support of their immune system. However, the breakthrough of biotechnology and its steady progress to develop and manufacture proteins, enzymes, monoclonal antibodies etc. will continue. This technology has opened a great deal of hope for a better and a more targeted therapy of many forms of cancer and especially rare diseases/genetic disorders. Hundreds of start-up companies compete for the support of investors. Some will succeed as the pioneers, which achieved worldwide success so far, namely Genentech (Roche), Amgen, Genzyme (Sanofi), Alexion Pharmaceuticals and others. The know-how of these successful biotechnology companies is based on their fundamental research as well as the production, isolation and purification of natural products (proteins, enzymes, monoclonal antibodies etc.) from cell cultures. Nobody else than the plasma protein fractionators had more experience and knowhow in this area. But unfortunately with the exception of Baxter and Bayer most plasma protein manufacturers missed the train to become important biotechnology companies. There are some exceptions, but astonishingly, the smaller plasma fractionators are much more courageous and are investing more money in R+D to regain the advantage they had in the past. 5. No plasma products without voluntary whole blood and plasma donors Ruedi E. Wäger, Ph. D. (Swiss Federal Institute of Technology, Zurich) The author is a former member of the Executive Committee of Sandoz Pharmaceuticals Inc., Basle, with worldwide responsibility for Marketing and Project Management; former President and CEO of ZLB, Central Laboratory of the Blood Transfusion Service Swiss Red Cross, Bern; former President and CEO of Centeon/Aventis Behring worldwide, King of Prussia, PA (USA) and member of the Board of Directors of several worldwide leading companies in the plasma protein (Aventis Behring, Talecris Biotherapeutics), medical device (Guidant Corp.) and biotechnology (Alexion Pharmaceuticals and others) business in the USA. As the blood transfusion service of the Swiss Red Cross (see chapter 3), many other national Red Cross societies (Germany, Belgium, Finland, USA, Japan and many more) and national blood transfusion services (UK, France, Netherlands etc.) started to organize the national supply of the hospitals with blood products through the collection of whole blood from voluntary donors. Many of these organizations started sooner or later inspired by the success of the Swiss Red Cross and its foundation ZLB to fractionate the blood plasma not needed for the immediate supply of hospitals into stable plasma protein products (Netherlands, Belgium, Finland, Germany, France, Japan etc.). Prof. Hässig played an important role in helping these organizations to make the transition from blood transfusion to blood transfusion plus plasma fractionation. In any case, he offered the ZLB technologies to these organizations. However, most of these national fractionation centers never achieved the critical size for an efficient and cost-covering manufacturing scale (between and liters of plasma fractionated per year, depending on the number of plasma products recovered from a liter of plasma) to survive. Some companies survived thanks to heavy subsidies by the government and the taxpayers but most of the companies were shut down or taken over by commercial plasma manufacturers. However, a few small companies survived the worldwide consolidation process for so-called ethical reasons (refusal of products manufactured from plasma donated by compensated donors and ban of importation of those products e. g. in France, claim for national self-sufficiency with blood products e. g. in Japan, financing of losses of the local plasma product manufacturers by the governments and the taxpayers respectively in France, UK). Many Red Cross (USA, Germany) and national transfusion services supply today local (Japan, France) or the worldwide leading commercial plasma product manufacturers (Baxter, CSL Behring, Grifols, Octapharma, Biotest, Kedrion) with the plasma, which is not used for the immediate supply of the hospitals. The plasma of voluntary non-remunerated blood donations is used for the manufacturing of fresh-frozen plasma for transfusion in the hospitals (roughly 50% of the total amount of plasma available after the separation from the red cells, platelets etc.). The other 50% of the plasma are shipped to plasma product manufacturers for fractionation. This plasma is called recovered plasma. The total volume of plasma from voluntary non-remunerated blood and plasma donations collected by the Red Cross and other national blood transfusion services mainly in the USA and Europe was approximately 18 mio. liters in 2012 (5). 8.9 mio. liters of recovered plasma were processed in the plasma fractionation plants of not-for-profit and commercial manufacturers which represent roughly 25% of the product supply and demand of/for life-saving products. 75% or 29 mio. liters of plasma were collected by the big plasma manufacturers and their suppliers from voluntary, compensated plasma donors, mainly in the USA (where 85% of the total amount of this type of plasma was collected) and organizations in Europe (mainly in Germany and Austria) and in Asia. This type of plasma is called source plasma. It is donated by voluntary, compensated donors and is collected by plasmapheresis, i. e. contrary to the whole blood donations by voluntary, non-remunerated blood donors (400 to 500 ml of whole blood per donation), an automated medical device removes whole blood, separates the plasma from the other blood components and then returns those components to the donor. These plasma donors are compensated for their travels to the plasmapheresis centers and the time of the plasma donation (approx. 2 hours of time). Without the plasma donations of voluntary compensated donors, 75% of the patients often young children in need of life-saving plasma products could not be treated accordingly: A scenario which is just unthinkable and unacceptable despite the wishful thinking and the idealistic dreams of many organizations about the ideal blood and plasma donation SWISS PHARMA 36 (2014) Nr. 3 9

12 Pharmaceutical Production / Biotherapeutics / Blood plasma products (which is in their eyes the voluntary, non-remunerated blood or plasma donation). The fact is very simple: Patients suffering from severe diseases have the right to be treated in the best possible way and according to the highest standards of medicine. To debate the origin of plasma (voluntary, non-remunerated donors of whole blood or plasma vs. voluntary, compensated plasma donors) is absolutely meaningless and far from the reality of patient needs. There is another important fact: Red Cross and national blood transfusion services see voluntary, non remunerated blood donors 2 to 4 times a year for their donation. Voluntary, compensated plasma donors appear normally every 7 to 10 days at their plasmapheresis center (the total number of plasma donations per donor and per year is limited in most European countries to approximately 35 donations per year). Although the requirements for both kinds of donors are nearly identical (health check, questionnaire regarding potential virus contamination risks and other safety issues), it is evident that the voluntary, compensated donors are followed much more closely by the plasma donation centers. It is also evident, that the donors are not showing up at a plasma center for the compensation for their plasma donation only: The large majority of these donors want just to make a meaningful contribution to the treatment of patients in need. The advantages and disadvantages of both kinds of blood/plasma donations (voluntary, non-remunerated whole blood donation and voluntary, compensated plasma donation) were discussed fiercely during decades. Sometimes, this debate escalated to a kind of religious war without any reason, I have to say. First and most importantly, both kinds of whole blood and plasma donations are safe and are not doing any harm to the donors. This is scientifically proven. But both kinds of donations offer a great deal of benefit for the patients in need. There is no doubt that the voluntary, non-remunerated whole blood or plasma donation remains a kind of ideal. However, most Red Cross and national blood transfusion services are fighting hard to keep the supply of blood products at the level of immediate need by the hospitals. The plasma left for plasma fractionation and the supply of life-saving products like albumin, immunoglobulins, alpha-1-antitrypsin etc. would cover roughly 25% of the real patient needs. This is not acceptable indeed. It is more ethical to insist on voluntary, non-remunerated blood and plasma donations just for a matter of principle or is it more ethical to do everything possible to provide patients worldwide with the life-saving therapies they really need? In addition, both forms are regulated and controlled/inspected by the relevant national health authorities (e. g. FDA, EMEA, etc.). The high level of professionalism and self-responsibility of the blood/ plasma collectors and manufacturers as well as the oversight of the relevant authorities resulted in an extremely high level of safety and reliability for the donors and the patients, As long as these prerequisites are fulfilled, the access of patients to therapy is the real priority. However, some countries still refuse to recognize these facts and ban or restrict the import and distribution of plasma products manufactured from plasma of voluntary, compensated plasma donors. The most prominent countries are France and Japan. The reasons are not completely clear although both countries make a claim for ethical reasons. In reality, it may be a modern form of protectionism for the national plasma product manufacturers in France (LFB) and Japan (Red Cross and others). Japan declared the objective of self-sufficiency for all blood and plasma products more than ten years ago without having ever achieved this goal. The position of the Japanese health au- Sterile filling of plasma products 10 SWISS PHARMA 36 (2014) Nr. 3

13 Pharmaceutical Production / Biotherapeutics / Blood plasma products Modern immunoglobulin purification facility thorities is understandable to some extent. The country was hit hard by virus infections of patients (especially hemophilia patients) through plasma products manufactured in Japan or imported in the 1980ies. However, I am not so sure whether the conclusions of the authorities are the right ones. Competition and innovation, from wherever they may come, are probably a better insurance to be on the safe side instead of closing the borders for whatever reasons. It is also interesting to note that LFB, the national plasma manufacturer in France, has recently acquired a plasma collection company in Austria specialized in the collection of voluntary, compensated plasma donations. Most likely, this plasma collected in Austria is transferred to France for the manufacturing of plasma products by LFB, which may be eventually exported to other countries afterwards. Is this a credible way to do business under the so-called strict ethical principles of the country? I sincerely hope, that none of these regulators and administrators claiming for these so-called ethical principles will ever suffer harm from the non-availability of the safest and highest quality plasma products. There is another important concern: Of course, each country has the legitimate right to decide what will be best for it. However, if countries decide to claim self-sufficiency or close the border for reasons of protectionism, they may run the risk that they will not get access to the most up-to-date technologies from abroad either. This is particularly important in the plasma industry, where many experts worldwide are working hard and effectively on the continuous improvement of safety (virus inactivation of new pathogens) and product quality. As mentioned before, today most big plasma product fractionators/manufacturers collect the plasma needed by their professional and dedicated own plasma collection units or buy the plasma from service companies. Centeon/Aventis Behring was the first big plasma product manufacturer that collected all the plasma needed for manufacturing (more than 3 mio. liters) in the U.S., Germany and Austria by its own dedicated plasma centers. This vertical integration approach has the great advantage that the plasma product manufacturer has immediate access to all data relevant from a safety and quality point of view at any time from the donor s vein (donor information, virus testing results etc.) to the final product. In 2012, the big plasma product manufacturers (Baxter, CSL Behring, Grifols, Octapharma, Biotest etc.) owned 387 of the 504 plasma centers in the U.S. and Europe. 6. Blood testing for virus infections of blood and plasma donors Today, all blood and plasma donations are tested for eventual virus infections (hepatitis A, B, C, HIV etc.). Contrary to the early 1980ies, when these tests were either not yet available or not reliable enough, the tests used today are much more sensitive and absolutely reliable. This progress was possible due to a new and steadily improved technology, PCR (polymerase chain reaction). This technology was conceived in 1983 by Kary Mullis who received the 1993 Nobel Prize in Chemistry at Cetus Corporation, in Berkley, California, USA, and first published by R. Saiki et al. (Cetus Corporation) in 1985 (6). F. Hoffmann-La Roche Inc. ac- SWISS PHARMA 36 (2014) Nr. 3 11

14 Pharmaceutical Production / Biotherapeutics / Blood plasma products quired the worldwide rights and patents for PCR from Cetus Corporation in PCR produces multiple copies of a specific nucleotide sequence from a target segment of DNA. It provides a mechanism to detect extremely low concentrations of the target DNA sequences (e. g. from infectious viruses or other pathogens) with high specificity. F. Hoffmann-La Roche and Roche Molecular Diagnostics have continuously improved this technology and developed very sophisticated and reliable systems for the end user, especially for the blood transfusion services and the plasma collection centers. Cobas Amplicor is a worldwide reference for the most reliable PCR testing technology. Cobas Amplicor and Roche Molecular Diagnostics have certainly helped to bring blood transfusion and plasma product therapy to a new, un-known level of safety. These achievements represent another very important contribution of a Swiss company to the worldwide progress of medicine and therapy of patients. 7. Manufacturing and quality management in the plasma industry Despite the fact that the centrifugation of the thawed plasma for the harvesting of cryoprecipitate for the production of factor VIII and the following fractionation of the remaining plasma with ethanol in the cold (based on the differential solubility at different ph levels) are straightforward processes, the manufacturing process in the plasma industry remains extremely complex and challenging. First, it is a matter of the starting material, namely human plasma. Thousands of plasma donations have to be pooled for a single batch and each donation in each pool has to be tracked back from the final product to the individual plasma donor. This allows the manufacturer to take the appropriate actions (e. g. quarantine, product recall etc.) if e. g. a plasma donor should be identified later on with a potential virus infection or any other health issues. By the way, for this reason, the first plasma donation of a new donor is never used for manufacturing before the same donor is coming back again and his second plasma donation is not tested positive for a virus infection. In addition, each individual plasma donation is held/stored for at least 60 days before being pooled for manufacturing. This allows the manufacturer to retrieve the plasma donation of a potentially infected donor (having been tested positive at a later donation) before the start of the manufacturing process. Second, each plasma pool and each manufacturing batch have to be fully documented with the information on all donors (and their blood testing results) who contributed with their plasma to the relevant pool and batch respectively. Third, the sterile filling of products, which are administered intravenously or intramuscularly, is always a true challenge for all pharmaceutical companies. Last but not least, since the virus infections of patients with blood plasma products in the early 1980ies, which generated so much harm and pain for the patients and their families, all companies learned their lessons and made every effort necessary to improve the safety of their products and to prevent any viral infections from plasma products. An increasing number of viral inactivation steps have been integrated into the manufacturing processes and have been validated for their efficacy: heat treatment/pasteurization (albumin and factor VIII), solvent-detergent and ph 4 treatment (immunoglobulins), ultra-filtration and nano-filtration (most plasma protein products). The newest virus inactivation procedures with caprylate have even proven to be effective to eliminate prions, which may lead to Creutzfeld-Jacob disease. The success and sustainability of each plasma product manufacturer depend on the safety of the products and the reliability of its quality management. Fortunately, those performances have increased significantly. During the last few years, no single infection/ contamination of any plasma product recipient has been reported for any product of the worldwide leading manufacturers. This is a great achievement indeed. In the late 1990ies, the FDA in the USA changed the rules of the game. Instead of stringent quality controls at the end of the manu- The worldwide plasma protein market and the sales of the different product categories (without recombinant factors) 2012 (8) 12 SWISS PHARMA 36 (2014) Nr. 3

15 Pharmaceutical Production / Biotherapeutics / Blood plasma products The worldwide market shares of the leading plasma product manufacturers (without recombinant factors) 2012 (8) facturing process, continuous controls of all manufacturing procedures and processes (i. e. monitoring of each step in the production) were requested. Most of the plasma product manufacturers were not well prepared for this shift of paradigm and had to pay a high prize for it: warning letters, consent decrees, business interruption and hundreds of millions of financial losses. However, all the companies concerned as well as the industry association PPTA (Plasma Protein Therapeutics Association) focused on new programs in all areas (selection of plasma donors, procedures for plasma donations and plasma testing, manufacturing incl. plasma logistics, virus inactivation in the manufacturing process and quality management/ oversight). Today, this industry and its companies are stronger than ever before and they are on a high level of alert for new challenges in any area in the future. For the reasons mentioned above (critical minimum fractionation scale, number of products fractionated from one single liter of plasma, availability of worldwide distribution systems, requirements for the quality systems in plasma collection and plasma fractionation etc.) the consolidation process in the worldwide plasma industry accelerated significantly over the last few years. Some notfor-profit plasma fractionators exited the business or were acquired by other companies. The number of plants operated by not-forprofit manufacturers decreased from 35 in 2002 to 25 in 2012, whereas the number of plants in the commercial sector increased from 45 to 52 during the same period of time (7). This trend is also documented by the available fractionation capacities of all plants worldwide: The capacity in the commercial sector increased from 24.2 mio. liters in 1999 to 40.5 mio. liters in 2012, whereas the capacity of the plants in the not-for-profit sector decreased from 9.7 mio. liters to 9 mio liters in the same period of time (7). The commercial sector expanded the fractionation capacity considerably, whereas the capacity of the not-for-profit fractionators remained nearly unchanged on a low level. This probably means, that the consolidation process in the industry is not yet completed. Whether the big commercial companies (Baxter, CSL Behring and Grifols) will be able to participate in this process remains an open question due to anti-trust regulations. But anyway, these companies may have other strategies to grow, prosper and to innovate. 8. The worldwide plasma product market in 2012 The more products (albumin, immunoglobulins, factors VIII and IX, specialty products like AT III etc.) are manufactured from a single liter of plasma, which costs approx US$, the better the economic perspectives for a manufacturer. For these reasons and thanks to their broad product portfolio, Baxter-Immuno and Centeon/Aventis Behring had by far the best starting positions to become worldwide leaders. Baxter is still the worldwide leader, whereas Bayer (parent of Bayer Biological Product Division) and Aventis (today part of Sanofi, at that time parent company of Centeon/Aventis Behring) decided to quit the plasma product business since the synergies with their main strategic focus, namely innovative pharmaceutical products, became too marginal. This was in fact the happy hour of the newcomers, CSL of Australia and Grifols of Spain. Both companies had a long tradition and presence in this business but were rather local (Australia and Spain) or regional (Asia and Europe respectively) players. However, both companies had a vision and an ambition to become worldwide leaders and they made this ambition a reality during the consolidation of the plasma product industry. CSL acquired ZLB in Switzerland and Aventis Behring in the USA. Grifols on the other hand bought Alpha Therapeutics in Los Angeles, California, and later on Talecris Biotherapeutics Inc. in Raleigh, North Carolina, the former Biological Product Division of Bayer that was turned around by private equity firms (Cerberus Capital Management and Ampersand respectively) before. Both companies, CSL Behring and Grifols, did a great job to integrate the acquired and much bigger units and SWISS PHARMA 36 (2014) Nr. 3 13

16 Pharmaceutical Production / Biotherapeutics / Blood plasma products are now worldwide leaders together with Baxter. It remains to be seen whether these companies have also a vision for the innovation process, which will ultimately decide on her long-term success. The first chance, to exploit the know-how for a big entry into the biotechnology business, which definitely represents an important part of the health care future, was missed. May be, there will be a second or more chances to enter new technologies of the future or new areas of innovation which will advance human health. The worldwide market for plasma products (without recombinant products/factors VIII, IX etc.) was bio. US$ in The recombinant products/factors achieved sales of 6.65 bio. US$ in 2012 (8). To put the size of the plasma product market in perspective: The worldwide pharmaceutical market achieved sales of 962 bio. US$ in Within the category of plasma-derived products, the immunoglobulins (for intravenous and subcutaneous application) achieved sales of 7.25 bio. US$ in 2012 which represent 47.6% of the total sales of the plasma industry. This segment will grow dynamically in the future as well. Albumin sales were in 2012 at a level of 2.02 bio. US$ (13.3% of the industry sales) and plasma-derived FVIII/F IX sales were at 1.61 bio. US$ (10.6% of the industry sales). Plasma-derived blood clotting factors were and are continuously replaced by recombinant factors in the developed world, but they will still expand in developing countries. Overall, their sales will not change dramatically. Albumin however has still a significant potential to grow, especially after the most recent medical studies which put some negative light on hydroxyethyl starch (HES) products. Also the specialty products (Alpha-1-antitrypsin, AT-III, C1-esterase inhibitors, fibrin sealants, etc.), which achieved sales of 2.94 bio. US$ in 2012 (19.3% of the industry sales), will grow further dynamically. These products (except the fibrin sealants which are used in the surgery settings) are often prescribed for the treatment of orphan diseases, i. e. severe genetically conditioned health disorders. Many of these products may still have a potential in other health disorders as well (8). The most important markets for plasma products in 2012 were North America (43.2%), Europe (30.8%) and Asia (14.2%) (8). The leading manufacturers of plasma products in 2012 were CSL Behring with a worldwide market share of 24.9%, Baxter (24.5%), Grifols (21.6%) and Octapharma (7.8%). The not-for-profit manufacturers (Red Cross and national blood transfusion services, mainly in Japan, France, United Kingdom and the Netherlands) achieved 2012 a worldwide market share of 12.1% (8). Baxter remains the leading company due to its strong position with recombinant factors VIII and IX (8). gross margins and therefore a better viability of most companies. Hopefully, the industry will invest adequate resources in R+D, in both areas plasma products and biotechnology in the future: Without this strategic investment, the growth and prosperity of the leading players may be threatened. The focus on the existing business is perfectly fine, but attractive business opportunities outside the plasma product market may help the companies to exploit existing strengths for future success. 10. Acknowledgements I thank Dr. J.-J. Morgenthaler for his critical review of the manuscript and Mr. Patrick Robert from The Marketing Research Bureau, Inc., Orange, CT/USA, for offering me the permission to use data and figures from his 2012 reports on the worldwide plasma industry ( International Directory of Plasma Fractionators 2012 and The Worldwide Plasma Proteins Market 2012 ). REFERENCES (1) Cohn E.J., Strong L.E., Hughes W.L. et al., Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J. Am. Chem. Soc. 1946; 68: (2) Poole J.G. and Shannon A.E., Production of antihaemophilic globulin in a closed bag system. NEJM 1965; 273:1443 (3) Remigy E., Essais de traitement par plasma cryoconcentré. University of Nancy, Academic thesis (4) Kistler P. und Nitschmann H., Large scale production of human plasma fractions. Vox Sang. 1962; 7: (5) Robert P., The Marketing Research Bureau Inc., Orange, CT/USA, persönliche Mitteilung (6) Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G., Ehrlich H. and Arnheim N., Enzymatic amplification of beta-globin genomic sequences and restriction site analysis of sickle cell anemia. Science 1985; 230: (7) Robert P., The International Directory of Plasma Manufacturers 2012, The Marketing Research Bureau, Inc., Orange, CT/USA (8) Robert P., The Worldwide Plasma Proteins Market 2012, The Marketing Research Bureau Inc., Orange/USA 9. Outlook The consolidation of the plasma products industry and the increased focus of the leading manufacturers on this core business start to pay back. The successful integration of the acquired companies, the increased number of products manufactured from a single liter of plasma, the vertical integration of the plasma collection and testing, the significant efforts of the industry to improve the existing products and their yield and to increase their (virus) safety and quality, led to a substantial improvement of the availability of the products for patients in need and to more attractive Contact address: Ruedi E. Wäger, Ph. D. (Swiss Federal Institute of Technology, Zurich) 8, chemin Morin CH-1253 Vandoeuvres / Geneva Switzerland Phone: +41 (0) SWISS PHARMA 36 (2014) Nr. 3

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